Lupus and Your Kidneys. Michael P. Madaio, MD Professor of Medicine Chairman of Medicine Medical College of Georgia Augusta, Georgia

Transcription

1 Lupus and Your Kidneys Michael P. Madaio, MD Professor of Medicine Chairman of Medicine Medical College of Georgia Augusta, Georgia

2 Kidney Inflammation and Abnormal Function as a Result of Lupus (Lupus Nephritis) Types of lupus nephritis Current treatment options Latest clinical study results Newer therapies Predicting treatment response

3 Major Types of Lupus Nephritis Lupus nephritis is grouped into 6 major types or classes (Class I-VI) Class I and II Mesangial Class III Focal Class IV Diffuse Class V Membranous Class VI Advanced sclerotic The higher the Class number, the more advanced the disease Injuries to the kidney (lesions) are also labeled as active or chronic Active lesions can be treated, chronic lesions cannot Advanced kidney disease is also known as end-stage renal disease

4 How does my doctor determine if I have lupus nephritis and what type of lupus nephritis I have?

5 Tests to Determine Class of Lupus Nephritis Blood tests provide clues Elevation in serum creatinine or BUN levels Greater the amount of anti-dsdna Lower the amount of complement More protein appears in urine These changes alert the physician to be more aggressive with diagnosis and treatment Tissue sample (kidney biopsy) amount of inflammation (potentially reversible, treatable) amount of scarring (irreversible)

6 Lack of correlation of Anti-DNA Antibody Levels and Severity of Lupus Nephritis 50 IgG DS-DNA I II III IV V Okamura et.al.annals of the Rheumatic Diseases. 52(1):14-20, 1993 Jan.

7 Treatment for Lupus Nephritis

8 Treatment - Lupus Nephritis Options Steroids Methylprednisolone (IV) or prednisone (oral) May be given at intervals (pulsed) Dose typically reduced over time Cytoxan (cyclophosphamide) Intravenous (IV) or oral Imuran (azathioprine) CellCept (mycophenolate mofetil MMF) Other immunosuppressive medication Clinical Trials

9 Prevention of Advanced Renal Disease Combination Therapy is Superior ESRD Less likely Intravenous Cytoxan Oral Cytoxan + Imuran Oral Cytoxan Imuran Similar Effect ESRD More likely Months Prednisone Steinberg AD. Arthritis Rheum. 1991;34:

10 Long-term Follow-up Likely that therapy would succeed Combination therapy still more effective after 10 years Combination therapy Cytoxan alone Likely that therapy would fail Solumedrol alone Months From Study Entry Illei GG, et al. Ann Intern Med. 2001;135:

11 Long-term Follow-up of Protocol Completers in WHO Class IV LN Dialysis Doubling SCr 50% Rise SCr Patients (%) MP alone (n = 24*) CY alone (n = 21) MP + CY (n = 20) *14 of 24 patients received CY after study completion Illei GG, et al. Ann Intern Med. 2001;135:

12 Standard Treatment 2001/2002 Pulse of IV Cytoxan with a pulse of Solumedrol every month for 6 months then again every third month thereafter Cytoxan + Solumedrol Time (months)

13 Long-term Cytoxan Therapy Improves Remission Rates In one study, the longer patients were on Cytoxan the more likely they were to go into remission 78% Patients Reaching Remission (%) % Median 50% 58% Months 10 Months 12 Months 24 Months Ioannidis JP, et al. Kidney Int. 2000;57:

14 Starting Cytoxan Early Reduces Relapse Rates Early Treatment < 5 months to Rx 75% free from relapse Delayed Treatment > 5 months to Rx 40% free from relapse Time After Cytoxan Was Stopped (Years) Ciruelo E, et al. Arthritis Rheum. 1996;39:

15 Event Cytoxan (n = 21) Combination Therapy (n = 20) High blood pressure 10/20 10/20 Heart disease limiting blood flow to heart 1/19 4/19 Elevated fat in blood (hyperlipidemia) 7/20 8/19 Heart disease affecting flaps that regulate blood flow 9/19 7/21 through the heart Tissue death resulting from lack of blood supply 6/21 6/20 Bone fragility (osteoporosis) 4/18 3/19 Premature menopause 9/16 10/18 Major infections 7/21 9/20 Herpes zoster infection 6/21 5/20 Illei GG, et al. Ann Int Med. 2001;135: n/n n/n

16 What are the factors that determine who will respond well to drug therapy for lupus nephritis?

17 Predicting Results Some groups of patients respond better to therapy than others Risk factors for progression to renal disease and renal failure Higher initial blood values of creatinine Mild anemia African-American Severe activity and chronicity (kidney biopsy) Austin HA, et al. Kidney Int. 1994;45:

18 Predicting Results (Cont d) Tissue extractions (biopsies) are important predictors of outcome Follow up biopsy in individuals that do not respond is important for future treatment If the biopsy after 6 months of treatment still shows that the disease is progressing, you may be placed on a different therapy Austin HA, et al. Kidney Int. 1994;45:

19 Worse Outcomes in African-Americans Non African-American Years From Renal Biopsy African-American Kidney function was less likely to be maintained in African-American patients Dooley MA, et al. Kidney Int. 1997;51:

20 What about alternative approaches to induction? Do we always need to treat with Cytoxan?

21 CellCept vs Oral Cytoxan Plus Imuran (Cont d) Complete Remission Partial Remission 14% 14% 81% 76% CellCept Group 1 Cytoxan Plus Imuran Group 2 Relapse 15% 11% Both treatments were effective, but fewer infections with CellCept Infection 19% 33% Patients (%) Chan TM, et al. N Engl J Med. 2000;343:

22 Relapse-free Survival After Achieving Remission in Patients with DPLN Chan, TM et al. J Am Soc Nephrol Apr;16(4):

23 Induction and Maintenance Therapy for Lupus Nephritis?

24 Probability of Freedom From Death or Chronic Renal Failure Renal failure less likely CellCept Imuran Similar Benefit Over Cytoxan 0.50 IV Cytoxan Renal failure more likely Months Contreras G, et al. New Eng J Med 2004.

25 Side Effects of Therapy Hospital Days Per Patient Year Loss of Menstruation (%) Infection (%) Major (%) IV Cytoxan Imuran 1* 7.5* 28* 3 CellCept 1* 6.1* 21* 3 Contreras G, et al. New Eng J Med 2004.

26 Oral CellCept vs IV Cytoxan Patients randomly assigned to groups Multiple centers involved Mostly female African-American patients with Class III or IV lupus nephritis Treatment groups Oral CellCept IV Cytoxan Measured remissions and partial remissions Ginzler E, Appel, et al. New Eng J Med 2005

27 CellCept vs Cytoxan Remission Rates Percent (%) Responding More complete remissions with CellCept 37/71 P = NS 21/71 21/69 16/71 17/69 CellCept IV Cytoxan 10 4/69 0 Complete Remission Partial Remission Complete + Partial Remission Similar results when African-American patients analyzed separately Ginzler E, Appel, et al. New Eng J Med 2005

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29 Novel Approaches - Lupus Nephritis Directed antibody therapy Anti-CD20 Anti-BLyS Anti-CD40 Anti-C5 Anti-IL10 Anti-IFN-γ Biomarkers

30 Take Home Messages Early diagnosis and therapy are important Combination therapy with steroids and immunosuppressive agents (e.g. cytoxan, MMF, immuran) improves results (e.g. better survival and fewer side effects) Outlook for African-Americans is better than ever New treatments are being developed and tested, and many look promising